Reports are limited on video-assisted thoracoscopic surgery for lung malignancy of patients with situs inversus totalis (SIT). Patients with SIT have significant anatomic differences with implications that are important for surgery, anesthesia, and nursing to understand in order to provide care for this patient population.

A 64-year-old man with SIT and lung adenocarcinoma needed flexible bronchoscopy and wedge resection of a 9×8 mm adenocarcinoma in the right upper lobe and underwent video-assisted thoracoscopic surgery.

Preoperative planning, including collaboration with the surgical team, allowed safe monitoring, induction of anesthesia, and airway isolation in this patient allowing them to have successful resection of their pulmonary malignancy. Postoperative care was enhanced by detailed communication and understanding of the patient's anatomy and implications of this condition for post anesthesia care unit nursing care.

Patients with rare clinical conditions and backgrounds may require surgical and anesthetic intervention. The authors describe important anesthetic considerations of preoperative evaluation, airway management, cardiac monitoring, and vascular access that should be noted and taken into account for patients with SIT. Proper preparation, planning, and communication allow for patients with SIT to safely undergo surgical procedures.

Situs inversus totalis (SIT) may be an incidental finding in asymptomatic children. Patients may not understand the implications of this condition and the importance of relaying the diagnosis to their healthcare providers.

We report an asymptomatic seventeen-year-old adolescent with previously-diagnosed SIT who presented for a routine well-child visit. During history taking, he denied any past medical conditions, including cardiovascular conditions. Only when physical exam revealed point of maximal impulse and heart sounds on the right side, did he convey that he had been diagnosed with SIT incidentally at age of 12 years. He was not aware of associated conditions or the potential implications of his diagnosis, nor did he realize it is pertinent medical history to be relayed to healthcare providers. Chest X-ray confirmed dextrocardia and abdominal X-ray showed right-sided stomach. Abdomen sonogram showed left-sided liver and right-sided spleen. Echocardiogram showed normal valvular structure and function. A comprehensive discussion was provided to address the patient's lack of understanding that SIT is a medical diagnosis with potential implications.

While SIT is rare and mostly asymptomatic, affected patients may not comprehend the importance of the diagnosis and its potential ramifications. Recognition of the patient's lack of awareness allows the healthcare provider to educate the patient and hopefully can prevent potential medical and surgical complications.

Bivalves are species-rich mollusks with prominent protective roles in coastal ecosystems. Across these ancient lineages, colony-founding larvae anchor themselves either by byssus production or by cemented attachment. The latter mode of sessile life is strongly molded by left-right shell asymmetry during larval development of Ostreoida oysters such as Crassostrea hongkongensis. Here, we sequenced the genome of C. hongkongensis in high resolution and compared it to reference bivalve genomes to unveil genomic determinants driving cemented attachment and shell asymmetry. Importantly, loss of the homeobox gene Antennapedia (Antp) and broad expansion of lineage-specific extracellular gene families are implicated in a shift from byssal to cemented attachment in bivalves. Comparative transcriptomic analysis shows a conspicuous divergence between left-right asymmetrical C. hongkongensis and symmetrical Pinctada fucata in their expression profiles. Especially, a couple of orthologous transcription factor genes and lineage-specific shell-related gene families including that encoding tyrosinases are elevated, and may cooperatively govern asymmetrical shell formation in Ostreoida oysters.

Classic appendicitis is a common condition easily diagnosed by emergency care providers. However, atypical cases represent a diagnostic challenge and can contribute to increased morbidity from a delay in definitive care. It is important to recognize that atypical presentations have an increased risk for underlying anatomic variants, which may require additional imaging as part of management. We present a case of a 13-year-old previously healthy adolescent boy with acute onset of left-sided abdominal pain who was found to have appendicitis in the setting of underlying malrotation.

Nodal signaling is essential for mesoderm and endoderm formation, as well as neural plate induction and establishment of left-right asymmetry. However, the mechanisms controlling expression of Nodal pathway genes in these contexts are not fully known. Previously, we showed that Cdx1b induces expression of downstream Nodal signaling factors during early endoderm formation. In this study, we show that Cdx1b also regulates epithalamic asymmetry in zebrafish embryos by modulating expression of ndr2 and lft1. We first knocked down cdx1b with translation-blocking and splicing-blocking morpholinos (MOs). Most embryos injected with translation-blocking MOs showed absent ndr2, lft1 and pitx2c expression in the left dorsal diencephalon during segmentation and pharyngula stages accompanied by aberrant parapineal migration and habenular laterality at 72 ​h post fertilization (hpf). These defects were less frequent in embryos injected with splicing-blocking MO. To confirm the morphant phenotype, we next generated both zygotic (Z)cdx1b^-/- and maternal zygotic (MZ)cdx1b^-/- mutants by CRISPR-Cas9 mutagenesis. Expression of ndr2, lft1 and pitx2c was absent in the left dorsal diencephalon of a high proportion of MZcdx1b^-/- mutants; however, aberrant dorsal diencephalic pitx2c expression patterns were observed at low frequency in Zcdx1b^-/- mutant embryos. Correspondingly, dysregulated parapineal migration and habenular laterality were also observed in MZcdx1b^-/- mutant embryos at 72 hpf. On the other hand, Kupffer's vesicle cilia length and number, expression pattern of spaw in the lateral plate mesoderm and pitx2c in the gut as well as left-right patterning of various visceral organs were not altered in MZcdx1b^-/- mutants compared to wild-type embryos. Chromatin immunoprecipitation revealed that Cdx1b directly regulates ndr2 and lft1 expression. Furthermore, injection of cdx1b-vivo MO1 but not cdx1b-vivo 4 ​mm MO1 in the forebrain ventricle at 18 hpf significantly downregulated lft1 expression in the left dorsal diencephalon at 23-24 ​s stages. Together, our results suggest that Cdx1b regulates transcription of ndr2 and lft1 to maintain proper Nodal activity in the dorsal diencephalon and epithalamic asymmetry in zebrafish embryos.

We herein describe the previously unreported combination of partial anomalous venous connection to the superior vena cava combined with situs inversus totalis. Following peripheral contrast injection, bubbles appeared initially in the left atrium allowing the diagnosis of a supra-atrial connection to be made using transthoracic echocardiography, but this timing was not anymore reproduced during transesophageal echocardiography performed minutes later. Cardiac computed tomography allowed the final diagnosis to be made. This case emphasizes the importance of performing bubble studies both during transesophageal and transthoracic echocardiography.

Situs inversus totalis is a rare congenital anomaly in which position of the heart and all abdominal viscera is reversed. Situs abnormalities usually go unnoticed but may be recognized by radiography or ultrasonography as an incidental finding or during evaluation for congenital heart diseases. We present such an extremely rare and to the best of our knowledge the third reported case of an injured spleen in the right hypochondrium, following seemingly trivial blunt trauma in a patient with situs inversus totalis who underwent splenectomy. The presence of associated congenital heart defects, visceral anatomical variations and mirror imaging makes the anaesthetic management as well as the surgical exercise a challenging one in such cases.

A case of unilateral pulmonary hypoplasia in association with abdominal situs inversus (Situs Inversus Partialis) is described here in a 2-mo-old baby. The normally related heart (levocardia) is dextroposed due to the hypoplastic right lung and compensatory hyper-inflation of the opposite lung which clinically mimicked a mirror-image situs inversus totalis. Such a combination, to the best of authors' knowledge, has never been reported in the world literature.

Polysplenia syndrome (PS) is rarely encountered in elderly. It is characterized by multiple spleens associated with various cardiac and gastrointestinal abnormalities including partial or complete agenesis of dorsal pancreas. Situs inversus totalis (SIT) is a rare congenital anomaly with mirror image of viscera combined with dextrocardia. Occurrence of SIT and PS in the same patient is exceedingly rare. We present the first case of adult PS with SIT accompanied with annular pancreas.

Situs inversus totalis is a rare condition characterized by a mirror-image transposition of the abdominal and thoracic viscera. In order to develop safe techniques for hepatic resection, it is important to report surgical outcomes in cases complicated by situs inversus totalis and other anomalies.

The patient was a 64-year-old man with situs inversus totalis who had previously undergone sigmoidectomy with regional lymphadenectomy for sigmoid colon cancer at age 62. Despite postoperative adjuvant chemotherapy, tumor markers increased and multiple liver metastases were detected on abdominal ultrasonography. Enhanced computed tomography revealed not only liver metastases but also hepatobiliary anomalies associated with situs inversus totalis as follows: (1) portal vein located anterior to the common bile duct or hepatic artery, (2) proper hepatic artery arising from the superior mesenteric artery, (3) "left" (right in normal population)-sided umbilical portion of the portal vein and total ramification of intrahepatic portal branches from that point, (4) hepatic vein directly communicating to the "left" atrium. For the treatment of hepatic metastases from sigmoid colon cancer in a patient with situs inversus totalis, "left" hepatic lobectomy, partial hepatectomy, and radiofrequency ablation therapy were performed. The postoperative course was uneventful. Adjuvant chemotherapy has been continued for 2 years after the second operation and the patient is doing well without recurrence.

Since situs inversus totalis is occasionally accompanied by multiple hepatobiliary anomalies, careful evaluation of the related anatomy using modern imaging modalities is crucial for safe hepatic resection.

Ten percent of people are left handed, but a higher frequency has been associated with certain craniofacial malformations, such as cleft lip and unilateral coronal synostosis. The purpose of this study was to determine the frequency of left-handedness in patients with hemifacial microsomia (HFM). Patients with HFM were identified in our craniofacial database. Normal controls were recruited by local pediatricians. Data gathered included age, sex, and handedness (determined by writing and/or drawing); the orbit, mandible, ear, nerve, and soft tissue (OMENS)-plus score and side of involvement were tabulated for patients with HFM. Hand preference was compared between the groups using chi analysis; possible correlations were analyzed between handedness and age, sex, the OMENS score, extracraniofacial findings, and side of involvement. One hundred seventy-eight patients with HFM were identified; 92 (51%) were excluded. Of the 86 included, 48% were boys (n = 47) and the mean age at inquiry was 13.5 years. Predominant side of involvement was right in 49% (n = 42) and left in 38% (n = 33). Eleven patients (13%) had severe involvement of both sides. Expanded-spectrum HFM was documented in 41% of patients. Ninety-six children were in the control group; 44% were boys (n = 42), and the mean age was 10 years. The difference in age between the groups was significant (P < 0.05), but sex differences were not. Patients with HFM were more likely to be left handed for writing compared with the control group (26% vs. 11%; P < 0.05). The frequency was higher, 36%, in those with bilateral involvement (P > 0.05). There was no correlation with predominant side or OMENS score. This study confirms that this disorder affects cerebral lateralization.

Failure to establish normal left-right body axis (LRA) formation during embryogenesis results in heterotaxis, a multi-malformation syndrome. We report on a 20-year-old young woman who presented to the emergency room with upper abdominal pain. On chest X-ray, dextrocardia was noted. Ultrasound was inconclusive. Barium studies demonstrated non-rotation of the intestine. Magnetic resonance imaging (MRI) of the abdomen confirmed heterotaxis with abnormal arrangement of abdominal organs and vasculature. This is the first radiographic description of LRA in MRI. It provides a unique contribution to the wide morphological variety of lateralization defects in a single examination within 15 min and without the risks of ionizing radiation. In addition, a literature overview over the genetic aspects, broad morphological spectrum, and possible therapeutic consequences is given.

The risk for a cardiac anomaly in a twin pregnancy is increased, particularly in monochorionic twins. This is relevant in terms of fetal diagnosis as well as for the management of the pregnancy; there are also implications for the neonatal period and possibly beyond. The risk for a cardiac abnormality depends on the type of monochorionic twin as determined by the timing of embryonic division. Prenatal identification of twin type and the relative risks for a cardiac anomaly are discussed along with theories for the aetiology of the different cardiac lesions.

In this paper, we describe the first reported case of a laparoscopic Nissen fundoplication and gastrostomy tube for gastroesophageal reflux disease in a 3-month-old infant with complete abdominal situs inversus.

Left-right asymmetry of internal organs is widely distributed in the animal kingdom. The chick and mouse embryos have served as important model organisms to analyze the mechanisms underlying the establishment of the left-right axis. In the chick embryo many genes have been found to be asymmetrically expressed in and around the node, while the same genes in the mouse show symmetric expression patterns. In the mouse there is strong evidence for an establishment of left-right asymmetry through nodal cilia. In contrast, in the chick and in many other organisms left-right asymmetry is probably generated by an early-acting event involving membrane depolarization. In both birds and mammals a conserved Nodal-Lefty-Pitx2 module exists that controls many aspects of asymmetric morphogenesis. This review also gives examples of divergent mechanisms of establishing asymmetric organ formation. Thus there is ample evidence for conserved and non-conserved strategies to generate asymmetry in birds and mammals.

To determine the incidence of structural heart disease in at least one of a monochorionic (MC) twin pair excluding any cardiac effects of twin-twin transfusion syndrome (TTTS).

A cohort study of 165 sets of MC twins undergoing detailed fetal echocardiography in a tertiary unit over a 4-year period.

The overall risk of at least one of a MC twin pair having a structural congenital cardiac anomaly was 9.1% (15/165); for monochorionic diamniotic (MC/DA) twins, this figure was 7.0% (11/158) but for monochorionic-monoamniotic (MC/MA) twins the risk for at least one affected twin was 57.1% (4/7). If one of a pair of MC twins was affected, the risk to the other twin for a structural cardiac anomaly was 26.7% (4/15).

The incidence of structural heart disease in MC twins is increased, independent of TTTS. This justifies referral of these pregnancies for detailed fetal echocardiography as part of their assessment. If one twin is affected, the risk to the other twin is increased further.

Development of the primary and secondary lymphoid organs is a tightly controlled process. These tissues are highly organized to maximize efficiency of the immune response. Spontaneous and targeted mutations in laboratory mice have led to better understanding of the molecular interactions and signaling pathways essential to the development and organization of lymphoid tissues, and the functional consequences of loss or disruption of the normal structures. On the basis of studies of mutations in mice and other species, it has been determined that a wild-type allele of the Foxn1 gene is required for normal thymic development and function. The Tlx1, Bapx1, Tcf21, Wt1 and Dh genes are essential for development of the spleen, while mutations of Nkx2-3, Lta, Ltb, Ltbr, Map3k14, Relb, Tnf, Tnfrsf1a, Cxcl13, Blr1 (Cxcr5), or cpdm genes result in disruption of normal splenic microarchitecture. The requirements for organized lymph nodes vary according to anatomic location, but most rely on Id2 (Idb2) and Rorc, in addition to lymphotoxins and Tnfrsf11a, Tnfsf11, Relb, Map3k14, Cxcl13, and Blr1 genes. Development of Peyer's patches is dependent on Id2 and Rorc genes, lymphotoxins, and Relb, Map3k14, Il7r, and cpdm genes. Less is known about the requirements for nasal-associated lymphoid tissues (NALT), but Id2 is a requirement. Here we review abnormalities of lymphoid organ development in immunodeficient mutant mice, including spontaneous and targeted mutations of Id2, Rorc, Tnf, Tnfrsf1a, Lta, Ltb, Ltbr, Tnfrsf11a, Tnfsf11, Relb, Map3k14, IL7r, Blr1, and Cxcl13 genes.

Situs inversus totalis refers to a mirror-image reversal of the normal position of the internal organs. The recognition of concomitant anomalies, such as in the cardiac, venous, gastrointestinal, and urinary systems, is extremely important because these anomalies may disturb the surgical procedure for the concurrent disease in situs inversus totalis. The authors describe a case of successfully repaired abdominal aortic aneurysm with a false aneurysm of the right external iliac artery in situs inversus totalis. The coexistence of abdominal aortic aneurysm has been seldom encountered. The presence of anatomical anomalies significantly increases operative risk. The surgical management of patients with abdominal aortic aneurysm in situs inversus totalis is discussed.

A male infant is reported with bilateral low-set dysplastic ears, a severe cardiac defect, rib and vertebral anomalies, and intestinal malrotation. Karyotype and metabolic investigations were normal. Some clinical overlap with Goldenhar syndrome is observed but the symmetry of the facial features makes this diagnosis difficult to sustain. We feel this case may represent a previously undescribed condition, arising from abnormal development of the first and second branchial arches during embryonic life.

Heterotaxy results from failure of the developing embryo to establish normal left-right asymmetry. Typical manifestations include abnormal symmetry and malposition of the thoraco-abdominal organs and vessels, complex congenital heart disease and extracardiac defects involving midline-associated structures. The spleen is almost always affected, and there is syndromic clustering of the malformations corresponding to the type of splenic abnormality present. This review outlines the embryologic and genetic background of the heterotaxy syndrome as well as the characteristic anatomic features, clinical manifestations, and diagnostic clues of its two main presentations with asplenia or polysplenia.

The majority of nonsyndromic congenital heart defects (CHDs) are considered to follow a multifactorial model of inheritance. Multiple family members affected by CHD can occasionally be detected, and the involvement of several genetic loci interacting with environmental factors is suspected to be implicated. The DiGeorge/velo-cardio-facial syndrome related to microdeletion 22q11.2 (del22) is a genetic condition associated with CHD in most of the cases. We report here on five pedigrees of patients with del22, showing occurrence of nonsyndromic CHD in a first-degree relative of the proband case. Familial aggregation of syndromic and nonsyndromic CHD as observed in our series is to be considered as an unusual pattern of recurrence. The interaction between several different genes and environmental factors, a familial susceptibility predisposing to a specific cardiac malformation, or chance association can all be hypothesized searching an explanation for these particular observations.

Situs inversus is a rare condition of visceral transposition in which the spinal axis is rarely affected.

The authors report a patient with situs inversus totalis and Type II split cord malformation. The patient had no symptoms and presented with scoliosis.

Recent compelling evidence from animal models and human case reports has lead to hypotheses that defects of the midline and laterality defects (e.g., situs inversus) are etiologically related. Confirmation from additional case reports of situs inversus and split cord malformation could prove useful in determining a genetic locus for split cord malformations or implicating various chemical agents that are known to produce situs inversus as potential causative factors in the production of split cord malformations.

One hundred and twenty-five fetuses were identified as having an AVSD with normal venous connections, normal arterial connections and normal cardiac situs on fetal echocardiography. Fetal karyotype was known in 111 of these cases. The relative risk of fetal trisomy 21 at mid-trimester was 107 (95% CI 87-127) times the expected number of cases compared with risk from maternal age alone, and that for trisomy 21,18 or 13 was 95 (95% CI 79-109). This data may be useful in counselling pregnant women about risk of fetal karyotypic abnormality after a diagnosis of fetal AVSD.

It is increasingly recognized that mutations in genes and pathways critical for left-right (L-R) patterning are involved in common isolated congenital malformations such as congenital heart disease, biliary tract anomalies, renal polycystic disease, and malrotation of the intestine, indicating that disorders of L-R development are far more common than a 1 in 10,000 incidence of heterotaxia might suggest. Understanding L-R patterning disorders requires knowledge of molecular biology, embryology, pediatrics, and internal medicine and is relevant to day-to-day clinical genetics practice. We have reviewed data from mammalian (human and mouse) L-R patterning disorders to provide a clinically oriented perspective that might afford the clinician or researcher additional insights into this diagnostically challenging area.

Situs inversus is a rare condition of visceral transposition in which the spinal axis is rarely affected.

The authors report a patient with situs inversus totalis and type II split cord malformation. This patient had no complaints and presented with scoliosis.

Recent compelling evidence from animal models and human case reports has led to hypotheses that defects of the midline and laterality defects (e.g., situs inversus) are etiologically related. Confirmation from additional case reports of situs inversus and split cord malformation could prove useful in determining a genetic locus for split cord malformations or implicating various chemical agents that are known to produce situs inversus as potential causative factors in the production of split cord malformations.

A male newborn with pentalogy of Cantrell, tetralogy of Fallot, agenesis of the gallbladder, and polysplenia died at 3 days of age. Polysplenia was not previously reported in this association.

The Jing-Mai (variously translated as the Channel, Vessel or Meridians), as described by traditional Chinese medicine, probably exists and has represented the connections between various parts of human body during embryonic development. According to the Chinese theories, there are 14 major Jing-Mai within the human body, of which four are directly connected with the Heart.

The described paths of the four Jing-Mai were compared with features of congenital syndromes involving particular types of congenital heart defects.

Specific correlation seem to exist between such four Jing-Mai and known developmental mechanisms underlying various congenital heart defects: the Kidney Jing-Mai-ectomesenchymal tissue migration abnormalities; the Spleen Jing-Mai-situs and looping defects; the Heart Jing-Mai-abnormal cell death; the Small Intestine Jing-Mai (and the Heart Jing-Mai)-extracellular matrix anomalies.

The Chinese theories seem to provide some intriguing insights into the pathogeneses of congenital heart defects. The Jing-Mai seems to distinguish from, but nevertheless have a close relationship with the blood vessels. Utilization of the Jing-Mai will probably enable a better understanding and development of new treatments for cardiovascular diseases.

Magnetic resonance (MR) imaging has emerged as an important and growing means of cardiovascular imaging, with many advantages over other radiologic modalities, including excellent spatial and temporal resolution, lack of ionizing radiation, and noninvasiveness. In this article, the utility of MR imaging in cardiovascular imaging and in the diagnosis of cardiovascular disease will be discussed. MR techniques for evaluating the heart and vasculature will be described, and troubleshooting techniques will be presented. Imaging findings in congenital anomalies such as septal defects, patent ductus arteriosus, transposition of the great arteries, and tetralogy of Fallot will be identified. Valvular lesions and methods for evaluating valvular function will be discussed. MR imaging findings in acquired disorders such as aneurysms and pericardial disease will be described.

We present a patient with heterotaxy and a de novo, apparently balanced reciprocal translocation with breakpoints at 6q21 and 20p13. Another patient with heterotaxy was previously reported with a de novo balanced translocation involving chromosome band 6q21. The breakpoints in both patients on 6q21 were found to be located in the same chromosomal region spanning maximally 2 Mb. We speculate that the two breakpoints lead to the disruption of the function of a single gene, either directly or through long distance effects. Alternatively, the present observation suggests additional heterogeneity in heterotaxy in humans.

The differential diagnosis of left lower quadrant abdominal pain in an adult man includes, among others, sigmoid diverticulitis; leaking abdominal aortic aneurysm; renal colic; epididymitis; incarcerated hernia; bowel obstruction; regional enteritis; psoas abscess; and in this rare instance, situs inversus with acute appendicitis. We report a case of situs inversus totalis with left-sided appendicitis and a brief review of the literature. There were several subtle indicators of total situs inversus present that were missed by the physicians and surgeons who initially evaluated the patient prior to surgery. Computed tomography scan with contrast, however, revealed the diagnosis immediately, and treatment was successfully initiated.

The causes of congenital heart malformations are complex and include a major contribution by genetic factors. These can be considered under the headings of chromosomal, single gene and multifactorial. Almost any degree of autosomal imbalance, whether a full trisomy or a tiny microdeletion, can cause a cardiac malformation. Recent research has identified several developmental genes which play an important role in cardiac formation: these are discussed with regard to laterality, septation and vascular morphogenesis. Hypothetical 'polygenes', which may contribute to non-syndromal 'multifactorial' cardiac malformations have yet to be identified. Well-known cardiac malformation syndrome associations are described and simple guidelines are presented to help in the assessment and investigation of an affected neonate who has additional multiple dysmorphic features.

The etiology of situs inversus totalis remains uncertain. However, the literature establishes that isolated situs inversus totalis is usually asymptomatic in the neonate. This case study illustrates the importance of physical assessment skills in identifying situs inversus totalis in the neonate. Current research may reveal the etiology of this rare but fascinating abnormality.

To provide insight into the possible etiology and prevalence of heterotaxy, we studied conditions associated with heterotaxy in a consecutive hospital population of newborns.

From 1972 to March, 1999 (except February 16, 1972 to December 31, 1978), 58 cases of heterotaxy were ascertained from a cohort of 201,084 births in the ongoing Active Malformation Surveillance Program at the Brigham and Women's Hospital. This registry includes livebirths, stillbirths, and elective abortions. Prevalence among nontransfers (i.e., patients whose mothers had planned delivery at this hospital) was calculated as approximately 1 per 10,000 total births (20 of 201,084).

We analyzed a total of 58 patients consisting of 20 (34%) nontransfers and 38 (66%) transfers. Patients were categorized by spleen status as having asplenia (7 nontransfers, 25 total), polysplenia (8, 20), right spleen (4, 11), normal left (0, 1), and unknown (1, 0). Among the 20 nontransfer and 59 total heterotaxy patients, the following associated medical conditions were present: chromosome abnormality (1 nontransfer, 2 total), suspected Mendelian or chromosome microdeletion disorder (1 nontransfer, 6 total), and maternal insulin-dependent diabetes mellitus (1 nontransfer, 2 total). There were 6 twins (1 member each from 6 twin pairs including 1 dizygous, 4 monozygous, 1 conjoined; 2 were nontransfers). An associated condition occurred in 5 (25%) nontransfer and 16 (28%) total patients, or among 10 of 53 singleton births (19%).

Although most cases of heterotaxy in this series were sporadic events, an associated condition was present in about one-fourth of the cases. Not all of these conditions would be considered causative etiologies. Based on this small series alone, maternal insulin-dependent diabetes cannot be viewed as a risk factor for heterotaxy. However, the specific association of diabetes with polysplenia with/without left atrial isomerism is noteworthy, and adds weight to animal and epidemiologic case-control data.

Primary ciliary dyskinesia is an autosomal recessive condition characterised by chronic sinusitis, bronchiectasis, and subfertility. Situs inversus occurs in 50% of cases (Kartagener syndrome). It has an estimated incidence of 1 in 20 000 live births. The clinical phenotype is caused by defective ciliary function associated with a range of ultrastructural abnormalities including absent dynein arms, absent radial spokes, and disturbed ciliary orientation. The molecular genetic basis is unknown. A genome scan was performed in five Arabic families. Using GENEHUNTER, a maximal multipoint lod score (HLOD) of 4.4 was obtained on chromosome 19q13.3-qter at alpha (proportion of linked families) = 0.7. A 15 cM critical region is defined by recombinations at D19S572 and D19S218. These data provide significant evidence for a PCD locus on chromosome 19q and confirm locus heterogeneity.

The extracardiac defects in patients with heterotaxy have not been examined as extensively as cardiac defects. We found a high incidence of midline-associated defects in 160 autopsied cases of heterotaxy (asplenia, polysplenia, or single right-sided spleen). Fifty-two percent of patients with left-sided polysplenia had a midline-associated defect, as did 45% of those with asplenia. Most common were musculoskeletal or genitourinary anomalies, as well as cleft palate. Fused adrenal glands and anal stenosis or atresia occurred exclusively among patients with asplenia. A midline anomaly was twice as likely to be detected on complete autopsy than from clinical findings alone. Linkage studies should take into account that affected subjects may have isolated subclinical midline defects. The high incidence of midline-associated defects supports the theory that the midline plays a critical role in establishing left-right asymmetry in the body. Comparison of these defects with mouse models of laterality defects suggests that mutations that disrupt the transforming growth factor beta pathway may result in heterotaxy.

The apparent symmetry of the vertebrate body conceals profound asymmetries in the development and placement of internal organs. Asymmetric organ development is controlled in part by genes expressed asymmetrically in the early embryo, and alterations in the activities of these genes can result in severe defects during organogenesis. Recently, data from different vertebrates have allowed researchers to put forward a model of genetic interactions that explains how asymmetric patterns of gene expression in the early embryo are translated into spatial patterns of asymmetric organ development. This model helps us to understand the molecular basis of a number of congenital malformations in humans.

Vertebrates develop distinct asymmetries along the left-right axis, which are consistently aligned with the anteroposterior and dorsoventral axes. The mechanisms that direct this handed development of left-right asymmetries have been elusive, but recent studies of mutations that affect left-right development have shed light on the molecules involved. One molecule implicated in left-right specification is left-right dynein (LRD), a microtubule-based motor protein. In the LRD protein of the inversus viscerum (iv) mouse, there is a single amino acid difference at a conserved position, and the lrd gene is one of many genes deleted in the legless (lgl) mutation. Both iv and lgl mice display randomized left-right development. Here we extend the analysis of the lrd gene at the levels of sequence, expression and function. The complete coding sequence of the lrd gene confirms its classification as an axonemal, or ciliary, dynein. Expression of lrd in the node at embryonic day 7.5 is shown to be symmetric. At embryonic day 8.0, however, a striking asymmetric expression pattern is observed in all three germ layers of the developing headfold, suggesting roles in both the establishment and maintenance of left-right asymmetries. At later times, expression of lrd is also observed in the developing floorplate, gut and limbs. These results suggest function for LRD protein in both ciliated and non-ciliated cells, despite its sequence classification as axonemal. In addition, a targeted mutation of lrd was generated that deletes the part of the protein required for ATP binding, and hence motor function. The resulting left-right phenotype, randomization of laterality, is identical to that of iv and lgl mutants. Gross defects in ciliary structure were not observed in lrd/lrd mutants. Strikingly, however, the monocilia on mutant embryonic node cells were immotile. These results prove the identity of the iv and lrd genes. Further, they argue that LRD motor function, and resulting nodal monocilia movement, are required for normal left-right development.

Defects of lateralisation have previously been recognised in the offspring of women with type-1 diabetes. In a 3-year period, three of the six cases of left isomerism sequence notified to the Northern Region Congenital Abnormality Survey were the infants of diabetic mothers. This finding suggests a specific association between bilateral left-sidedness and maternal type-1 diabetes.

We report on two sib fetuses, products of a consanguineous union, who had multiple and apparently unrelated malformations. The first fetus, a female, had trilobed lungs, a single cardiac ventricle, asplenia, situs ambiguus of the liver, and a lumbosacral meningomyelocele. The brain of this fetus was normal. The second fetus, a male, had bilobed lungs, a single cardiac ventricle, situs solitus of the abdominal organs and spleen, and a semilobar holoprosencephaly. The occurrence of these malformations in sibs of different sexes and the parental consanguinity suggest a recessive mutation in a gene responsible for both heterotaxy and midline defects, including holoprosencephaly.

Visceral left-right asymmetry occurs in all vertebrates, but the inversion of embryo turning (inv) mouse, which resulted following a random transgene insertion, is the only model in which these asymmetries are consistently reversed. We report positional cloning of the gene underlying this recessive phenotype. Although transgene insertion was accompanied by neighbouring deletion and duplication events, our YAC phenotype rescue studies indicate that the mutant phenotype results from the deletion. After extensively characterizing the 47-kb deleted region and flanking sequences from the wild-type mouse genome, we found evidence for only one gene sequence in the deleted region. We determined the full-length 5.5-kb cDNA sequence and identified 16 exons, of which exons 3-11 were eliminated by the deletion, causing a frameshift. The novel gene specifies a 1062-aa product with tandem ankyrin-like repeat sequences. Characterization of complementing and non-complementing YAC transgenic families revealed that correction of the inv mutant phenotype was concordant with integration and intact expression of this novel gene, which we have named inversin (Invs).